EP2873670A1 - Complexes de zirconium bis azainositol pour imagerie par rayons X - Google Patents

Complexes de zirconium bis azainositol pour imagerie par rayons X Download PDF

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EP2873670A1
EP2873670A1 EP20130192945 EP13192945A EP2873670A1 EP 2873670 A1 EP2873670 A1 EP 2873670A1 EP 20130192945 EP20130192945 EP 20130192945 EP 13192945 A EP13192945 A EP 13192945A EP 2873670 A1 EP2873670 A1 EP 2873670A1
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Prior art keywords
compound
coo
cyclohexane
bis
independently
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German (de)
English (en)
Inventor
Markus Berger
Detlev Suelzle
Thomas Frenzel
Hubertus Pietsch
Gregor Jost
Christian NEIS
Kaspar Hegetschweiler
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Universitaet des Saarlandes
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Bayer Pharma AG
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Priority to PCT/EP2014/074121 priority patent/WO2015071201A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/003—Compounds containing elements of Groups 4 or 14 of the Periodic Table without C-Metal linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to new bis azainositol Zirconium complexes comprising new azainositol ligands, to methods of preparing said compounds and to the use of said compounds as X-ray contrast agents.
  • Nycomed AS in WO 90/08138 described heterocyclic chelating agents for the preparation of diagnostic and therapeutic agents for magnetic resonance imaging, scintigraphy, ultrasound imaging, radiotherapy and heavy metal detoxification.
  • General Electric Company described nanoparticle compositions in WO 2012/080290 comprising metal oxides including Zirconium oxide and their potential use as contrast agents in medical imaging techniques such as X-ray.
  • This relates to an earlier report on dextrin-stabilized aquasols of Zirconium and Zirconium dioxides (Zirconotrast, Hafnotrast) in the context of their biokinetics ( Environmental Research 1979, 18, 127 ) and to US 5326552 X-ray imaging compositions based on Zirconium oxide nano particles.
  • Zirconium based x-ray contrast agent will be especially effective in contrast enhanced x-ray mammography performed with conventional projection imaging or with more advanced tomographic imaging methods like thomosynthesis or potentially dedicated breast computed tomography.
  • contrast to MRI based mammography the x-ray procedures today are usually performed without contrast agents.
  • contrast agents has the potential to increase the diagnostic performance of mammography procedures significantly.
  • the contrast agent available for intravascular administration today are not efficient in the x-ray energy range used for mammography.
  • Mammography imaging units operates with x-ray tube voltages in the range of 35 to 49 kV.
  • the respective x-ray energy spectra enable high imaging contrast to detect breast tumors/calcifications at lowest radiation dose.
  • the signal efficacy of the well-established iodinated x-ray contrast agents is rather low in this energy range.
  • Zirconium based contrast agents offers a significantly higher x-ray absorption (quantified by the mass-attenuation coefficient) for the x-ray energies used in mammography. Thus, contrast enhanced x-ray mammography will become feasible.
  • the use of Zirconium will also allow for energy subtraction imaging in digital mammography as described by Lawaczeck et al. (Investigative Radiology 2003, 38, 602 ).
  • the state of the art described above consists of physiologically stable or thermodynamically instable heavy metal complexes which hold a metal that is not suitable for the x-ray energy range used in mammography.
  • the aim of the present invention was to provide sufficiently stable, water soluble and well tolerated Zirconium complexes with a high metal content for use as X-ray contrast agents in diagnostic imaging, especially in the x-ray energy range used in mammography or in the energy subtraction imaging mode.
  • the compounds of the present invention are excreted fast and quantitatively via the kidneys, comparable to the well established triiodinated X-ray contrast agents.
  • the present invention describes a new class of trinuclear Zirconium complexes comprising two hexadentate azainositol carboxylic acid ligands, methods for their preparation and their use as low kV X-ray contrast agents.
  • the invention is directed to compounds of the general formula (I), wherein
  • the present invention includes all possible stereoisomers of the compounds of the present invention, as single stereoisomers, or as any mixture of said stereoisomers, e.g. R- or S- isomers, in any ratio.
  • Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention may be achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
  • Compounds containing chiral centers may be used as racemic mixture or as an enantiomerically enriched mixture or as a diastereomeric mixture or as a diastereomerically enriched mixture, and an individual stereoisomer may be used alone.
  • the present invention also relates to useful forms of the compounds as disclosed herein, such as hydrates, solvates, salts, in particular pharmaceutically acceptable salts, and co-precipitates.
  • Trinuclear Zirconium complexes of the general formula (I), which are charged at physiological pH, can be neutralized by addition of suitable, physiologically biocompatible counter ions.
  • Suitable anions are the anions of inorganic acids, such as, for example, hydrochloric acid, phosphoric acid and sulfuric acid, as well as the anions of organic acids, such as, for example, acetic acid, citric acid, aspartic acid, glutamic acid, among others can be used.
  • the compounds of the present invention can exist in the form of a salt.
  • Said salt may be any salt, either an organic or inorganic salt, particularly any pharmaceutically acceptable organic or inorganic salt, customarily used in pharmacy.
  • pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention.
  • pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention.
  • S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19 .
  • Pharmaceutically acceptable salts of the compounds according to the invention include salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • hydrochloric acid sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
  • the present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
  • the compounds of general formula (I) will conveniently be formulated together with pharmaceutical carriers or excipient.
  • the contrast media of the invention may conveniently contain pharmaceutical formulation aids, for example stabilizers, antioxidants, pH adjusting agents, flavors, and the like. They may be formulated for parenteral or enteral administration or for direct administration into body cavities.
  • parenteral formulations contain a sterile solution or suspension in a concentration range from 100 to 400 mg Zirconium/mL, especially 150 to 300 mg Zirconium/mL of the new azainositol heavy metal clusters according to this invention.
  • the media of the invention may be in conventional pharmaceutical formulations such as solutions, suspensions, dispersions, syrups, etc. in physiologically acceptable carrier media, preferably in water for injections.
  • the contrast medium is formulated for parenteral administration, it will be preferably isotonic or hypertonic and close to pH 7.4.
  • the invention also includes all suitable isotopic variations of a compound of the invention.
  • An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature.
  • isotopes that can be incorporated into a compound of the invention include isotopes of hydrogen, carbon, nitrogen and oxygen, such as 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 17 O and 18 O, respectively.
  • isotopic variations of a compound of the invention are useful in drug and/or substrate tissue distribution studies. Tritiated and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium may afford certain advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances.
  • isotopic variations of a compound of the invention can generally be prepared by conventional procedures known by a person skilled in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents.
  • the present invention covers compounds of general formula (I), supra, wherein :
  • the present invention covers compounds of general formula (I), supra, wherein :
  • the present invention covers compounds of general formula (I), supra, wherin :
  • Another embodiment of the first aspect are compounds of formula (I) selected from the group consisting of:
  • the invention is directed to the process for the preparation of the compounds of the general formula (I).
  • the invention is directed to the process for the preparation of the compounds of the general formula (I) supra, from carboxylic acids of the general formula (II), wherein
  • aqueous solution under elevated temperatures using conventional heating methods or microwave irradiation, ranging from 80°C to 180°C, in a pH range of 1 to 7, preferably at 110° to 160 °C in a pH range of 1 to 4.
  • the present invention also relates to a method of preparing a compound of general formula (I) supra, said method comprising the step of allowing an intermediate compound of general formula (II) in which
  • the invention is directed to compounds of general formula (I) for the manufacture of diagnostic agents, especially of X-ray diagnostic agents, for administration to humans or animals.
  • Another aspect of the invention is the use of the compounds of general formula (I) for the manufacture of diagnostic agents.
  • Another aspect of the invention is the use of a compound of general formula (I) for diagnostic imaging, especially as X-ray diagnostic agent.
  • Another aspect of the invention is the use of a compound of general formula (I) for use in the diagnosis of a disease.
  • Another aspect of the invention is the use of a compound of general formula (I) in the diagnosis of a disease.
  • Another aspect of the invention is the use of a compound of general formula (I) in the diagnosis of a cancer, especially in the diagnosis of breast cancer.
  • Another aspect of the invention is the use of a compound of general formula (I) as diagnostic agent.
  • the present invention provides carboxylic acid derived ligands based on 1,3,5-triamino-1,3,5-trideoxy-cis-inositol (taci) that can readily form trinuclear, highly stable Zirconium(IV) complexes with high water solubility.
  • the tri-O-benzylated taci derivative all-cis-2,4,6-tris(benzyloxy)-1,3,5-cyclohexanetriamine (tbca) was used as starting material throughout. It can be prepared as reported by Bartholomä et al. (Chem. Eur. J. 2010, 16, 3326 ).
  • the ligand tbca can be alkylated in the presence of bases like cesium carbonate or N,N-diisopropylethylamine with tert -butyl-halogenoacetate in organic solvents like THF or dichloromethane.
  • the ligand tacita was synthesized according to G. Welti (Dissertation, Switzerland 1998 ) using the tri- O -benzylated taci derivative tbca as starting material which was alkylated in the reaction with the sterically demanding agents N,N -diisopropylethylamine and tert -butyl-bromoacetate (Scheme 1).
  • the protecting groups were removed in boiling hydrochloric acid and pure H 3 tacita was isolated by precipitation at pH 5.5.
  • the statistically formed monoalkylation (tbcama) and dialkylation (tbcada) products are purified by preparative HPLC or by chromatography on amino phase silica gel.
  • the twofold derived ligand tbcada or the one fold derived ligand tbcama (Scheme 3) can be obtained as main product.
  • Introduction of the third amino substituent at the primary amine can be accomplished by reductive amination procedure or Michael addition of acrylic acid derivatives like acrylonitrile or acrylic esters.
  • Aldehydes or ketones can be used in combination with a suitable reducing agent like 5-ethyl-2-methylpyridine borane complex ( Tetrahedron Lett. 2008, 49, 5152 ), sodium triacetoxyborohydride or sodium cyanoborohydride ( Comprehensive Organic Synthesis, Pergamon: Oxford 1991, 8, 25 ).
  • a suitable reducing agent like 5-ethyl-2-methylpyridine borane complex ( Tetrahedron Lett. 2008, 49, 5152 ), sodium triacetoxyborohydride or sodium cyanoborohydride ( Comprehensive Organic Synthesis, Pergamon: Oxford 1991, 8, 25 ).
  • the available dimers can be used to deliver the subsequent tbcadamx derivatives (Scheme 4).
  • a third possibility to introduce a third substituent at the primary amine is the alkylation with halogenoalkanes in the presence of bases.
  • the pure ligands are conveniently obtained in the hydrochloride form by cation exchange chromatography after removal of the protecting groups under strong acidic conditions.
  • the ligand tacidpma with one acetic acid and two propionic acid as amino substituents can be prepared analogously by treatment with acrylonitrile or acrylic ester and subsequent acidic deprotection of the tbcadpma intermediate (Scheme 5).
  • the building block tbcadpn can be prepared from tbca using stoichiometric amounts of acrylonitrile.
  • Introduction of the third amino substituent different from already present substituents to the intermediate tbcadpmx can analogously to tbcadamx be introduced at the primary amino group by reductive amination of appropriate aldehydes or ketones or by halogen-alkanes in the presence of base. (Scheme 6).
  • the pure tacidpmx ligands can be obtained by simultaneous removal of the protecting groups and nitrile or ester hydrolysis under strong acidic conditions.
  • Trinuclear Zirconium(IV) complexes of the accordingly prepared ligands can be synthesized by adding stoichiometric amounts or minor excess of Zirconium salts like Zirconium(IV)chloride to aqueous solutions of the ligand (Scheme 7).
  • the reaction mixtures can be heated by conventional methods or by microwave irradiation at a pH range from 1 to 7 for at least 15 minutes at a temperature range from 110 °C to 160 °C under pressure.
  • Isolation and purification of the desired complexes can be achieved by preparative HPLC, ultrafiltration or crystallization methods.
  • Figure 1 Crystal structure of of [Zr 3 (H -3 tacitp) 2 ] (Example 2). The displacement ellipsoids are drawn at the 50 % probability level; H(-N) hydrogen atoms are shown as spheres of arbitrary size; H(-C) hydrogen atoms are omitted for clarity.
  • pH* refers to the direct pH-meter reading (Metrohm 713 pH meter) of the D 2 O samples, using a Metrohm glass electrode with an aqueous (H 2 O) Ag/AgCl-reference that was calibrated with aqueous (H 2 O) buffer solutions.
  • Elemental analyses (C,H,N) were recorded on a LECO 900V or VARIO EL analyzer.
  • Taci (2.0 g, 11.3 mmol) was dissolved in methanol (100 mL) and acrylonitrile (7.4 mL, 0.11 mol) was added. The solution was stirred for 24 hours at ambient temperature. The solvent was removed, the residue washed successively with diethyl ether and hexane and the white solid was dried in vacuo to yield 3.9 g (97 %) of tacitpn ⁇ 0.2H 2 O ⁇ 0.5CH 3 OH.
  • Tacitpn (3.8 g, 10.7 mmol) was dissolved in sodium hydroxide (10.3 g of a 25 % solution, 64.4 mmol) and heated to reflux for 4 hours. The solvent was removed and the residue was taken up in 1 M hydrochloric acid (5 mL) and sorbed on DOWEX 50. The column was washed with water (1 L), 0.25 M hydrochloric acid (1 L), 1 M hydrochloric acid (1 L) and the product was eluted with 3 M hydrochloric acid (1 L). The solvent was removed and the solid dried in vacuo to yield: 5.1 g (86 %) of H 3 tacitp ⁇ 3HCl ⁇ 3H 2 O.
  • H 3 tacitp ⁇ 3HCl ⁇ 3H 2 O (830 mg, 1.5 mmol) was dissolved in water (80 mL). 1 M sodium hydroxide (13.5 mL, 13.5 mmol) as well as Zirconium(IV) oxychloride octahydrate (805 mg, 2.5 mmol) dissolved in water (10 mL) were successively added. The pH was adjusted to ⁇ 3.5 (1 M hydrochloric acid) and the suspension was heated to reflux for 3 days. The solids were filtered off and to the filtrate was added mixed bed ion exchange resin Amberlite MB-6113 until the resin kept its blue color. The resin was filtered off and the filtrate was lyophilized. Single crystals suitable for X-ray structure analysis were obtained by slow evaporation of an aqueous solution of the metal complex to yield 450 mg (46 %) of [Zr 3 (H -3 tacitp) 2 ] ⁇ 15H 2 O.
  • H 3 tacitp ⁇ 3HCl ⁇ 3H 2 O (165 mg, 0.3 mmol) was dissolved in water (20 mL). 1 M sodium hydroxide (2.7 mL, 2.7 mmol) as well as Zirconium(IV) oxychloride octahydrate (161 mg, 0.5 mmol) dissolved in water (5 mL) were successively added. The pH was adjusted to ⁇ 3.5 (1 M hydrochloric acid) and the suspension was heated to reflux for 3 days. The solids were filtered off and to the filtrate was added mixed bed ion exchange resin Amberlite MB-6113 until the resin kept its blue color. The resin was filtered off and the filtrate was lyophilized to yield 140 mg (72 %) of [Zr 3 (H -3 tacitp) 2 ] ⁇ 15H 2 O.
  • H 3 tacitp ⁇ 3HCl ⁇ 3H 2 O 400 mg, 0.7 mmol was dissolved in a formaldehyde solution (37 %, 25 mL, 334 mmol) and palladium on charcoal (40 mg, 10 %) was added.
  • the reaction mixture was hydrogenated in an autoclave at 50 atm H 2 for 4 days at rt.
  • the reaction mixture was filtered off and the filtrate concentrated to dryness.
  • the residue was dissolved twice in a 1 : 1 mixture of water and formic acid (30 mL) and evaporated to dryness again.
  • the remaining solid was taken up in 3 M hydrochloric acid (10 mL) and sorbed on DOWEX 50.
  • Tbcama 300 mg, 0.5 mmol was dissolved in methanol (30 mL). Acrylonitrile (350 ⁇ L, 5.3 mmol) was added and the solution was stirred for 2 days at ambient temperature. The solvent was removed and tert -butyl N- ( ⁇ [1 R -(1 ⁇ ,2 ⁇ ,3 ⁇ ,4 ⁇ ,5 ⁇ ,6 ⁇ )]-2,4,6-tris[benzyloxy]-3,5-bis[(2-cyanoethyl)amino]-cyclohexane-1-yl ⁇ imino)acetate was obtained as crude product. The residue (350 mg) was suspended in 6 M hydrochloric acid (50 mL) and heated to reflux for 3 h.
  • Tbcada 500 mg, 0.74 mmol was dissolved in methanol (50 mL) and acrylonitrile (0.24 mL, 3.7 mmol) was added. The solution was stirred for 24 hours at ambient temperature. The solvent was removed, resolved in methanol, which was removed again. The residue was purified by chromatography on amino phase silica gel (ethyl acetate in hexane, 20 to 100%) to yield 447 mg of the title compound.
  • the stability of bis azainositol Zirconium complexes was determined in aqueous, buffered solution at pH 7.4.
  • the solution containing 5 mmol/L of the compound in a tightly sealed vessel was heated to 121 °C for 45 minutes in a steam autoclave.
  • the Zirconium concentration of the solution was determined by ICP-OES before and after heat treatment.
  • the integrity of the compound was determined by HPLC analysis before and after heat treatment. Absolute stability was calculated as the ratio of the peak area of the compound after and before the heat treatment multiplied with the ratio of the metal concentration of the solution after and before heat treatment.
  • Detector element specific detection by ICP-MS, running at m/z 90, the most abundant isotope of Zirconium. Chromatographic conditions Example No Stability Column Solvent A Solvent B Gradient Flow 1 2 3 100% 2 A2 B2 60 -15% B2 in 10 min 1 mL/min 4 100% 2 A2 B2 60 -15% B2 in 10 min 1 mL/min 5 6

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EP20130192945 2013-11-14 2013-11-14 Complexes de zirconium bis azainositol pour imagerie par rayons X Withdrawn EP2873670A1 (fr)

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PCT/EP2014/074121 WO2015071201A1 (fr) 2013-11-14 2014-11-10 Complexes de bis azainositol-zirconium pour l'imagerie radiographique

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0190676A1 (fr) 1985-02-02 1986-08-13 Laboratorien Hausmann AG Dérivés de cis-1,3,5-triamino 2,4,6-cyclohexanetriol, leur utilisation, leur procédé de préparation et préparations pharmaceutiques les contenant
WO1990008138A1 (fr) 1989-01-13 1990-07-26 Nycomed As Agents heterocycliques de chelation
WO1991010454A1 (fr) 1990-01-09 1991-07-25 Byk Gulden Lomberg Chemische Fabrik Gmbh Complexes d'elements de transition pour diagnostic par resonance magnetique
DE4028139A1 (de) 1990-09-05 1992-03-12 Hausmann Ag Labor Verwendung der komplexe radioaktiver metallionen mit all-cis-1,3,5-triamino-2,4,6-cyclohexantriol und seinen derivaten fuer roentgendiagnostische zwecke und in der tumortherapie sowie zur herstellung von mitteln fuer roentgendiagnostische zwecke und fuer die tumortherapie
US5326552A (en) 1992-12-17 1994-07-05 Sterling Winthrop Inc. Formulations for nanoparticulate x-ray blood pool contrast agents using high molecular weight nonionic surfactants
WO2012080290A1 (fr) 2010-12-15 2012-06-21 General Electric Company Composition de nanoparticules et procédés qui lui sont associés

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Publication number Priority date Publication date Assignee Title
EP0190676A1 (fr) 1985-02-02 1986-08-13 Laboratorien Hausmann AG Dérivés de cis-1,3,5-triamino 2,4,6-cyclohexanetriol, leur utilisation, leur procédé de préparation et préparations pharmaceutiques les contenant
WO1990008138A1 (fr) 1989-01-13 1990-07-26 Nycomed As Agents heterocycliques de chelation
WO1991010454A1 (fr) 1990-01-09 1991-07-25 Byk Gulden Lomberg Chemische Fabrik Gmbh Complexes d'elements de transition pour diagnostic par resonance magnetique
DE4028139A1 (de) 1990-09-05 1992-03-12 Hausmann Ag Labor Verwendung der komplexe radioaktiver metallionen mit all-cis-1,3,5-triamino-2,4,6-cyclohexantriol und seinen derivaten fuer roentgendiagnostische zwecke und in der tumortherapie sowie zur herstellung von mitteln fuer roentgendiagnostische zwecke und fuer die tumortherapie
WO1992004056A1 (fr) 1990-09-05 1992-03-19 Laboratorien Hausmann Ag UTILISATION DE COMPLEXES D'IONS METALLIQUES RADIOACTIFS AVEC all-cis-1,3,5-TRIAMINO-2,4,6-CYCLOHEXANTRIOL ET DE LEURS DERIVES A DES FINS DE DIAGNOSTIC RADIOGRAPHIQUE ET DE THERAPIE ANTI-TUMEURS, AINSI QUE POUR LA PRODUCTION D'AGENTS DE DIAGNOSTIC RADIOGRAPHIQUE ET D'AGENTS ANTI-TUMORAUX
US5326552A (en) 1992-12-17 1994-07-05 Sterling Winthrop Inc. Formulations for nanoparticulate x-ray blood pool contrast agents using high molecular weight nonionic surfactants
WO2012080290A1 (fr) 2010-12-15 2012-06-21 General Electric Company Composition de nanoparticules et procédés qui lui sont associés

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A. EGLI, DISSERTATION, 1994
BARTHOLOMA ET AL., CHEM. EUR. J., vol. 16, 2010, pages 3326
BARTHOLOMÄ, M.; GISBRECHT, S.; STUCKY, S.; NEIS, C.; MORGENSTERN, B.; HEGETSCHWEILER, K., CHEM. EUR. J., vol. 16, 2010, pages 3326
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HEGETSCHWEILER, KASPAR: "A rigid, cyclohexane-based polyamino-polyalcohol as a versatile building block for tailored chelating agents", CHEMICAL SOCIETY REVIEWS , 28(4), 239-249 CODEN: CSRVBR; ISSN: 0306-0012, 1999, XP002720628, DOI: 10.1039/A802638F *
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MORITZ ET AL: "Untersuchungen zur regulation des pentosephosphatweges in Corynebacterium glutamicum", BERICHTE DES FORSCHUNGSZENTRUMS. JUELICH, 1 January 1998 (1998-01-01), XP002154572, ISSN: 0944-2952 *
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